Basic alkoxyalkyl esters of phenothiazine-10-carboxylic acid



United States Patent BASIC ALKOXYALKYL ESTERS OF PHENOTI-H- AZINE-lO-CARBOXYLIC ACID Carl von Seemann, Westmount, Quebec, Canada, assignor to American Home Products Corporation, New York, N. Y., a corporation of Delaware No Drawing. Application July 13, 1955, Serial No. 521,927

9 Claims. (Cl. 260-243) These new chemical compounds maybe represented by the following general formula:

in particular where Alk represents a straight chain alkylene group containing 2 carbon'atoms, and R1 and R2 represent lower straight or branched chain alkyl groups. These alkyl groups may also be linked with each other directly to form a pyrrolidine or piperidine ring, or they may be linked through a further hetero atom such as oxygen to form a morpholine ring. In all cases these heterocyclic groups are attached to the alkylene group through nitrogen.

The new compounds are useful as medicinal agents. My novel basic alkoxyalkyl esters possess comparatively little atropine-like properties. as a relaxing agent for smooth muscle, which property seems to be a function of the ether linkage which is present in the basic ester group.

Novel basic esters of the specified generic, or type formula will form acid addition salts with a variety of inorganic and organic acids. Among such may be mentioned the acid addition salts with hydrochloric, hydrobrornic, sulfuric, maleic, oxalic, tartaric, citric, picric, and picrolonic acids, etc. The novel. basic esters will" also form quaternary ammonium salts such. as the methochloride, methobrornide, ethobromide, methi'odid'e, ethiodide, methosultate, etc. Both acid addition and quaternary ammonium salts are pharmacologically eftective.

In preparing the novel basic esters, a phenothiazine- 10-carboxylic acid halide may be reacted with the basical-v Their primary activity is.

mixture is then poured, on ice, the oily precipitate repea't'edly washed by decantation with ice;water,-taken up ester of phenothiazine-lO-carboxylic acid, which, after drying, may be obtained by evaporation of the solvent. The basically substituted alkoxyalkyl ester may be readily converted to an acid addition salt by dissolving it in an anhydrous inert solvent, such as ethyl ether, and precipitating it by the. addition to the solution of a small excess of the acid whose salt is desired, this acid being preferably added in the form of a solution thereof in an anhydrous inertsolvent which is miscible with the solvent in which the basically substituted alkoxyalkyl ester of phenoth-iazi'ne-IO-carboxylic acid is dissolved. This procedure results in the desired acid addition salt. Purification of the salt, may be eifiected by dissolving it under anhydrous conditions in a lower alcohol, such as methanol, or a lower ketone, such as acetone, and reprecipitating it from, the solution by the addition thereto of an inert solvent in which it is relatively insoluble such, for example, as ethyl ether.

The basically substituted alkoxyalkyl ester may also be read ly converted to a quaternary ammonium salt thereof. This may be done by reacting it in ananhydrous inert solvent, such as ethyl ether, with an excess of the appropriate alkyl halide or alkyl sulfate. The reaction is preferably carried out at a slightly elevated temperature, such as one within the range30.65 C. A periodof. from 1- to several days may bev needed for the; react-ion tobe complete. The precipitated, quaternary ammonium salts may be; purified by the sameprocedure asdescribedr above for the purification of the acid addition salts.

. The following examples are-illustrative of my invention.

5 Example 1 5.23 grams of phenothiazine-IO-carboxylic acid chloride were suspended in 16 grams of B'-diisopropylaminoethoxyethanol and heated, with stirring, underanhydrous conditions, first for 1 hour at a temperature of 50105 C., thenfor another hour at 108l10 C. All the suspended acid chloride had dissolved after thefinal heating, and the solutionwas. then allowed to cool slowly to C. over a period of one hour. Infra-red examination of a sample showed that theesterification reaction was essentially complete after the second hour. I

The reaction mixture was then poured on 1' liter of crushed ice, and the oily precipitate washed repeatedly by decantation with ice water. It was then taken up in 75 milliliters of benzene, and again washed repeatedly with water until a pH of 8.2 in the washings indicated that substantially all of the excess fi-diisopropylaminoethoxyethanol had been, removed; The benzene solution was then driedwith anhydrous sodium sulfate, filtered, and the benzene evaporated in a current of dry nitrogen gas. The residual dark oil constituted the desired basic ester, fi-diisopropylaminoethoxyethyl phenothiazine-IO- carb'oxylate.v

By following the procedure as described, but using 8 grams dirnethylaminoethoxyethanol and 9.7 grams diethylaminoethoxyethanol, ,B-dimethylaminoethoxyethyl phenothiazine-lO-carboxylate, and B-diethylaminoethoxyethylphen'othiazine-1.0-carboxylate were both obtained. 1-

Example 2 A sample of ddiisopropylaminoethoxyethyl phenothiazine-lO-carboxylate as obtained in Example 1 was dissolved in anhydrous ether and precipitated from the solutionby adding thereto a slight excess of an ethereal solution of picric acid. The resulting picrate salt was-repeatedly washed with dry ether. It was then purified, by repeatedly. redissolving it in anhydrous methanol, diluting,

andreprecipitating the saltby the addition of 15 volumes ofdry. etherto each solution. There was, thus obtained an. amorphous glassy product. Elementary analysis conanhydrous ether. ,60' C. in a sealed tube with an excess of methyl bromide, w

firmed its structure as p3-diisopropylaminoethoxyethyl phenothiazine-IO-carboxylate monopicrate, C29H33010N5S.

Example 3 Samples of the basic esters as obtained in Example 1 were dissolved in anhydrous ether and then precipitated by adding a slight excess of a solution of dry hydrogen chloride in ether. The resulting gums Were purified by the procedure described in Example 2 as applied to the corresponding picrate salt, and the hydrochloride salts isolated as amorphous, glass-like products, which could be crystallized from anhydrous acetone or from methanol-ether. In this manner there were obtained as stable, crystalline, colorless substances 3- dimethylaminoethoxyethyl phenothiazine-10-carboxylate hydrochloride, one sample of which melted at 161163 C. with decomposition, cal. for C19H2303N2S C1, Cl: 9.02%, found fl-diethylaminoethoxyethyl phenothiazine- 10-carboxylate hydrochloride, one sample of which melted at 182l83 C. with decomposition, cal. for C21H2103N2S C1, Cl: 8.42%, found Cl: 8.42%; and

B diisopropylaminoethoxyethyl phenothiazine 10 carboxylate hydrochloride, one sample of which melted at 149-150 C., cal. for C23H3103N2S Cl, Cl: 7.88%, found Cl: 7.83%.

Example 4 A sample of fi-diisopropylaminoethoxyethyl phenothiazine-IO-carboxylate as obtained in Example 1 was dis-- I solved in anhydrous ether, and to the solution there was then added a small excess of an ethereal solution of 'maleic acid. The resulting precipitatewas purified by following the procedure described in Example 2. B-diisopropylaminoethoxyethyl phenothiazine-10-carboxylatemaleate was thereby recovered, the salt being an amorphous, hygroscopic product as precipitated from the anhydrous methanol solution.

Example A sample of the basic ester, B-diisopropylaminoethoxyethyl phenothiazine--carboxylate, as obtained by the procedure described in Example 1, was dissolved in anhydrous ether and'the solution then treated with a small excess of an ethereal solution of tartaric acid. The resulting precipitate was purified by following the procedure described in connection with the purification and recovery of the corresponding picrate salt in Example 2. There 'was thus obtained the amorphous, hygroscopic tartrate salt of p-diisopropylaminoethoxyethyl phenothiazine-10- carboxylate.

. Example 6 By following the procedure described in Example 2, but utilizing initially an ethereal solution of oxalic acid instead of the ethereal solution of picric acid there emof picric acid used in Example 2) there was obtained the picrolonate of the basic ester. In each case the crude salts were washed with dry ether, and purified by repeatedly redissolving in anhydrous methanol, diluting, and reprecipitating the salts by the addition of dry ether to the diluted solutions, following the proportions and recovery procedure as described in Example 2.

Example 7 A sample of p-diisopropylaminoethoxyethyl phenothiazine-lO-carboxylate as prepared in accordance with the procedure described in Example 1 was dissolved in The resulting solution was heated to the heating being continued for 4 days. This resulted in a crystalline precipitate which was purified and recovered by following the procedure described in Example 2. Elemental analysis confirmed the crystalline product to be the quaternary ammonium salt, B-diisopropylaminoethoxyethyl phenothiazine-lO-carboxylate methobromide, one sample of which melted at 157-158 C. with decomposition, calc. for C24H33O3N2S Br, Br: 15.67%, found Br: 15.86%. By following the procedure as described, but starting with fl-dimethylarninoethoxyethyl phenothiazine 1O carboxylate and 13 diethylaminoethoxyethyl phenothiazine-10-carboxylate the corresponding methobromides were obtained; thus, fi-dimethylaminoethoxyethyl phenothiazine-10-carboxylate methobromide, one sample of which melted at 136-138 C. with decomposition, calc. for CzoHzsOsNzS Br, Br: 17.65%, found Br: 17.58%, and fl-diethylaminoethoxyethyl phenothiazine- IO-carboxylate methobromide, one sample of which melted at 134 C., calc. for CzzHzaOsNzS Br, Br: 16.62%, found,Br: 16.45%.

Various changes and modifications may be made in my invention as described which would still be within the scope of the above description. Such changes and modifications are intended to be included within the scope of the appended claims.

Iclaim:

1. A compound selected from the group which consists of the basic esters of the formula:

where Alk represents a straight chain alkylene group containing two carbon atoms, and R1 and R2 each represent lower alkyl; their acid addition salts with hydrochloric,

hydrobromic, sulfuric, maleic, oxalic, tartaric, citric, picric and picrolonic acids; and their methochloride, methobromide, ethobromide, methiodide, ethiodide and methosulfate quaternary ammonium salts.

2. A basic ester of the formula:

where Alk represents a straight chain alkylene group containing two carbon atoms, and R1 and R2 each represent lower alkyl.

3. fi-dimethylaminoethoxyethyl phenothiazine-IO-car- 6. fl-diisopropylaminoethoxyethyl phenothiazine 10 carboxylate.

7. fi-diisopropylaminoethoxyethyl phenothiazine- 10 carboxylate hydrochloride.

8. The process of preparing a compound of the forwhere Alk represents a straight chain alkylene group containing two carbon atoms, and R1 and R2 are each selected from the group which consists of lower straight chain alkyl groups and lower branched chain alkyl groups, which comprises bringing together, at an elevated temperature not exceeding C. and under substantially anhydrous conditions, phenothiazine-IO-carboxylic References Cited in the file of this patent acid chloride and a fi-di-(IOWGI' alkyD-aminoethoxy UNITED STATES PATENTS ethanol.

9. The process of preparing fl-diisopropylaminoethoxy- 2650919 Cuslc Sept 1953 ethyl phenothiazine- 10 -carboxylate which comprises 5 FOREIGN PATENTS bringing together, at an elevated temperature not ex- 708 896 Great Britain May 12 1 ceeding 120 C. and under substantially anhydrous conditions, phenothiazine-IO-carboxylic acid chloride and 13-diisopropylaminoethoxyethanol. 

1. A COMPOUND SELECTED FROM THE GROUP WHICH CONSISTS OF THE BASIC ESTERS OF THE FORMULA: 